13alpha-fluoro-17beta-methyl-18-nor steroids



United States Patent 3,210,388 ISa-FLUQRO-17fi-METHYL-18-NOR STEROIDS Lawrence H. Knox, Mexico City, Mexico, assignor to Syntex Corporation, Panama, Panama, a corporation 3,219,388 Patented Oct. 5, 1965 ICQ trophic and anti-fibrillatory properties, lower the blood cholesterol level and inhibit the activity of the pituitary gland.

The estrone derivatives are estrogenic type hormones of Panama 5 having anti-androgenic and anti-progestatiorral proper- No nmwi Filed Mar 23, 1964, Ser. No. 354,126 gfg g jf fig In addltw they are Clmms pnonty apphctmgaexlco July 1962 The substitution of primary and secondary hydroxyl 16 Cl i ((11, 260-3973,) groups by a fluorine atom has been described in the litera- 10 ture, for example, by N. N. Yarovenko et al. in the Jour- This application is a continuation in part of my copendnal of General Chemistry of the USSR, vol. 29, 2159 ing patent application Serial No. 221,424, filed September (1959). 5, 1962, now abandoned. In my copending patent application Serial No. 353,263,

The present invention relates to certain novel cyclofiled March 19, 1964, there has been described the transpentanophenanthrene derivatives and to the method for formation of Uri-secondary hydroxy steroids into a mixmaking the same. ture of 17x-fiuoro, 17fl-chlorofluoroacetoxy and 17,8- More particularly, it relates to a process for making methyl compounds, by reaction with 2-chloro-l,1,2-tricertain novel 13u-fluoro-17fi-methyl-18-nor derivatives of fluorotriethylamine. the androstane and estrane series represented by the fol- In accordance with the present invention the surprislowing formulas: 20 ing discovery has been made that when a 17a-hydroxy CH3 CH3 steroid of the androstane or estrane series is treated with F n the abovementioned a-fluorinated amine, in a suitable or- 5 E ganic solvent, the substitution of the hydroxyl group by RB fluorine occurs in a very small amount and in contrast, R the main products obtained by this reaction are the 130cfluoro-l7fi-methyl and 17B-methyl-A -compounds. There is also obtained a small amount of the l'l'oc-chlorofluoro- O acetoxy compounds.

' This method is illustrated by the following equation Z X wherein only rings C and D are depicted:

K, a 3 c"; e 1 F pct-GH In the above formulas R, R and R each represent hydrogen or methyl; R repreesnts a lower alkyl group,

Z represents a double bond or a saturated linkage between C-4 and C-5 and X represents hydrogen, methyl, chlorine or fluorine.

The present invention refers also to certain novel 17,8- methyl-A -l8-n0r, 17fi-fluoroand 17a-chlorofluoroacetoxy derivatives of the androstane and estrane series, which are obtained as by-products in practicing the process of the present invention.

The androstane compounds of the present invention are anabolic agents with a favorable anabolic-androgenic ratio; in addition they have anti-estrogenic, anti-gonado- The starting materials for the process of the present invention are epitestosterone, 19-nor-epitestosterone, androstan-17a-ol-3-one, 19-nor-androstan-17a-o1-3-one, the 2 or 6 substituted derivatives thereof, 1'7a-estradio1, 1- methyl-lh-estradiol whose hydroxyl group at C3 is protected in the form of an ether, preferably the methyl ether. By reaction of these compounds with 1 to 1.5 molar equivalents of 2-chloro-1,1,Z-trifluorotriethylamine in an inert organic solvent, at a temperature comprised between room temperature and reflux for a period of time between 30 minutes and 20 hours, followed by evaporation of the solvent and chromatography of the residue on Florisil or neutral alumina, there are produced the corresponding 3 13u-fluor0-l7/3-methyl-l8-nor, 17/3 methyl A 18-nor-, 17/3-fluoroand l7ix-chlorofluoroacetoxy compounds.

Adequate solvents for this reaction are acetonitrile; ethers such as diethylether, isopropyl ether, tetrahydrofuran, dioxane, Dowanol and the like; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; in general, the reaction can be carried out in any organic solvent without acidic hydrogen.

In addition to the aforementioned starting materials, the process of the present invention can be carried out using any l7u-hydroxy androstane or estrane compound having different substituents at C-2, C4, C-6, C7, etc., which do not react with the fluorinated amine; additional double bonds at C-1, 2, C-6, 7, etc. may also be present in the starting materials.

The following examples serve to illustrate but are not intended to limit the scope of the present invention:

PREPARATION I To a suspension of 7.5 g. of l7a-estradiol in 25 cc. of acetone there was added a solution of 70 g. of potassium hydroxide in 37.5 cc. of water and the stirred mixture was treated dropwise with 40 cc. of methyl sulfate. The reaction mixture was then stirred for 45 minutes further, poured into dilute hydrochloric acid solution and the formed precipitate collected by filtration. Crystallization from chloroform-methanol gave the 3-methyl ether of 1705- estradiol.

A cold solution of 6 g. of 17oi-estradiol-3-methyl ethe. in 750 cc. of anhydrous ether was added to 900 cc. of liquid ammonia and then 7.8 g. of lithium wire over minutes, with constant stirring. The mixture was stirred for 20 minutes more, 160 cc. of absolute ethanol were then cautiously added and the ammonia was allowed to evaporate. Water was added to the residue, the ether distilled ofi? and the resulting 3-methoxy-A -19-norandrostadien-lh-ol collected, washed with water and dried.

A mixture of the foregoing crude compound, 220 cc. of methanol and 132 cc. of 3 N hydrochloric acid was heated at 60 C. for 18 minutes. The solution was cooled, poured into iced water and the resulting precipitate was collected, washed with water and dried. Crystallization from acetone-hexane yielded the pure :l9-nor-epitestosterone.

PREPARATION II tered off, washed with benzene, then hexane, and dried for several hours in vacuo. The product was cautiously added in portions to a stirred ice-cold dilute hydrochloric acid solution, liberating the free ethoxyoxalate which was extracted with methylene dichloride. The extract was washed with water, dried and evaporated. The residue;-

was taken up in 110 cc. of acetone, 5 g. of finely powdered anhydrous potassium carbonate and 15 cc. of methyl iodide were added and the mixture 'boiled under reflux for 48 hours. The filtered solution was evaporated almost to dryness, water added, the residue extracted with methylene chloride and the extract washed with 1% sodium hydroxide solution, water, dried and evaporated to dryness. The residue was dried at 90 C. for 2 hours in vacuo and then treated with a solution of sodium ethoxide prepared from 0.5 g. of sodium and 50 cc. of absolute ethanol. The solution was allowed to stand for 48 hours at room temperature and then poured into 100 cc. of water. Without neutralization, the mixture was extracted with methylene dichloride and the organic extract washed with water to neutral, dried and evaporated. Chromatography of the residue on neutral alumina gave the pure 2a-methyl-A androsten-l7a-ol. (Zoe-methyl-epitestosterone.)

A mixture of 5 g. of epitestosterone, 60 cc. of 2-methyl- 2-ethyl-1,3-dioxolane and mg. of p-toluenesulfonic acid was heated to boiling and refluxed with distillation for 1 hour. The mixture was cooled, diluted with water, extracted with ethyl acetate and the organic extract washed to neutral, dried and evaporated to dryness. Crystallization from acetone-hexane yielded 3-ethylenedioxy A -androsten-l7u-ol.

A solution of 4 g. of the foregoing ketal in cc. of chloroform was cooled to 0 C. and mixed with 1.1 molar equivalents of monoperphthalic acid in ether solution. The mixture was kept at 0 C. for 20 hours, diluted with water, the organic layer was separated, washed with aqueous sodium bicarbonate solution and then with water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetone-hexane gave 3-ethylenedioxy-5a,6a-oxido-androstan-17a-ol.

To a solution of 40 cc. of 4 N methylmagnesium bromide in ether was added, with stirring, a solution of 2 g. of the preceding 5a,6a-oxido derivative in 50 cc. of dry tetrahydrofuran and the stirred mixture heated under reflux for 30 minutes. The condenser was then replaced by a calcium chloride tube, the ether allowed to boil off and when the internal temperature reached 54 C., the condenser was readapted and the mixture refluxed for an additional 4 hours. 200 cc. of a saturated solution of ammonium chloride was added slowly to the cooled mixture which was then stirred for 15 minutes before transfer to a separatory funnel. Ethylacetate was added, the organic layer separated, washed, dried and evaporated, whereupon crystallization of the residue from aqueous methanol gave 3-ethylenedioxy-6fi-methyl-androstane-5a,l7oc-diol.

Into a suspension of 1 g. of the foregoing compound in 35 cc. of glacial acetic acid, there was passed a slow stream of dry hydrochloric acid; after 10 minutes all the solid material was dissolved. The gas was passed through the reaction mixture for a total of 5 hours. The solution was concentrated to about one third its initial volume by distillation under reduced pressure at 35 C., then it was poured into ice-water. The precipitate formed was collect d, washed with water to neutrality and dried. Recrystallization from methylene chloride afforded 6ot-methyl-A -androsten-17a-ol-3-one.

By the same method, starting from l9-nor-epitest0sterone there was obtained Got-methyl-l9-nor-A -androstenl7a-ol-3-one as final product.

PREPARATION IV A suspension of 5 g. of epitestosterone in 40 cc. of anhydrousperoxide-free dioxane was treated with 6 cc. of

. fieshly distilled ethyl orthoformate and 4 g. of p-toluenesulfonic acid. The mixture was stirred at room temperature for 15 minutes and the resulting solution let stand for 30 minutes further. 4 cc. of pyridine were added and then water. The formed precipitate was collected by filtration, water washed and air dried. Recrystallization from acetone-hexane afforded 3-ethoxy-A -androstadien- 17oc-Ol.

A mixture of 5 g. of the foregoing compound, 2 g. of anhydrous sodium acetate and 100 cc. of acetone was treated with 32 cc. of water and the solution was cooled to a temperature between 0 and 5 C. There was then added 1.1 molar equivalents of N-chloro-succinimide and 2 cc. of glacial acetic acid and the mixture was stirred between 0 and 5 C. for 30 minutes. It was then diluted with water, kept overnight at 0 C. and the precipitate formed was collected, washed with water, dried under vacuum and recrystallized from acetone thus giving 6;?- chloro-A -androsten-17oz-ol-3-one.

Upon reaction of this 6B-chloro compound with hydrogen chloride in glacial acetic acid, in accordance with the PREPARATION V A solution of 2 g. of 3-ethoxy-A -androstadien-1704-01 in 50 cc. of dimethylformamide was cooled to C. and a stream of perchloryl fluoride was passed for minutes; the solution was allowed to come slowly to C.; it was then poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium bicarbonate, then with Water to neutrality, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was then treated with hydrogen chloride in acetic acid, to invert the steric configuration at C6, and the product purified by chromatography on neutral alumina. There was thus obtained 6ot-fluoro-A -androsten-17u-ol3-one.

By the same method, starting from 3-ethoxy-19-nor- A 'flI1dIOSt3ClleI1-17Dt-O1 there was obtained 6OL-flIlOI'O-19- nor-A -androsten-l7a-ol-3-one.

PREPARATION VI I II 2a-methy1-19-nor-A -androsten-17aol-3-one.

-0ne. (in-ehloro-A -androsten-17a-o1-3- one. Gwohloro-lQ-nor-N-androsten-l7a- Ol-3-0Il9.

6a-fiuoro-19-nor-androstan-17aol-3-one. 6a-chloro-androstan-17a-ol-3-one.

fia-chloro-lQ-nor-androstan-17aol-3-one.

PREPARATION VII A mixture of 5 g. of epitestosterone in 100 cc. of dioxane and 3.5 g. of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was refluxed for 10 hours. It was then cooled, the 2,3 dichloro 5,6 dicyano 1,4 benzohydroquinone formed during the reaction filtered off, and the filtrate evaporated to dryness. The residue was dissolved in acetone and filtered through 100 g. of alumina. Crystallization from acetone-hexane gave A -androstadien- 17a-ol-3-one.

A mixture of 3 g. of the foregoing diene, 600 mg. of p-toluenesulfonic acid and 120 cc. of acetic anhydride was heated for 5 hours on the steambath; the cooled solution was poured carefully onto ice water and the mixture stirred for minutes to elfect hydrolysis of the excess anhydride. The solid product was collected by filtration, washed with water and air dried, thus producing the 3,17- diacetate of 1-methyl-17a-estradiol.

A solution of 1 g. of the diacetate in cc. of 1% potassium hydroxide solution in methanol was refluxed for 1 hour, poured into water and the formed precipitate collected by filtration. Crystallization from chloroformmethanol gave the pure l-methyl-lh-estradiol.

6 Upon reaction of the preceding compound with dimethyl sulfate in the presence of alkali, in accordance with the method of Preparation I, there Was produced 1-methyl-3-methoxy-A -estratrien-17a-ol.

Example I.

A mixture of 8.7 g. of epitestosterone, 8.5 g. of 2- chloro-1,1,2-trifluorotriethylamine (1.5 molar equivalents) and cc. of anhydrous tetrahydrofuran was stirred at room temperature for 14 hours. It was then evaporated under vacuo at room temperature and the residue chromatographed on 400 g. of Florisil, thus producing in pure form 13a fluoro 17B methyl 18 nor A androsten-3-one, M.P. 118l19 C. [ot] +101 (CHCI Amax. 240-242 m log. 6 4.34; vinax. 1670, 1615 cm. (enone); 17p methyl 18 nor A androstadien 3-one; MP. 112113 C.; [0c] +69 (CHCI Amax. 238-240 m log. 6 4.23; small amounts of 17/3-fluoro- A -androsten-3-one and 17a-chlorofluoroacetoxy-A -androsten-3-one were also obtained.

Example 11 To a solution of 2 g. of epitestosterone in 50 cc. of methylene chloride there were added 1.5 molar equivalents of 2-chloro-1,l,Z-trifluorotriethylamine, and the reaction mixture was refluxed for 20 minutes under anhydrous conditions. Evaporation under reduced pressure and chromatography of the residue on Florisil afforded a fluoro 17,8 methyl l8 nor A androsten 3 one, 17,8 methyl 18 nor A4113 androstadien 3 one, 17,8 fluoro A androsten 3 one and 17a chlorofiuoroacetoxy-A -androsten-3-one, identical to the products obtained in the preceding example.

Example 111 Example I was repeated but using acetonitrile as solvent, with the same results.

Example IV Example II was repeated, but using ether as solvent, with the same results.

Example V I II 19-nor-androstan-17a-ol- 3-one.

2a-methyl-A -androstenza-methyl-androstan- 17a-ol-3-one.

2a-methy1-19-n0r-androstan-lM-oLB-one.

fia-methyl-M-androsten- 17a-ol-3-one.

I II

(ia-methyl-androstan- 6a,175-dimethyl-l3a-fluoro-18-nor-andro- 17a-ol-3-0ne. stan-3-one, 6a,175-dimethyl-18-norA Ga-methyLlQ-nor-M- androsten-17a-ol-3- one.

Ga-methyI-IQ-nOr-andmstan-17u-ol-3-one.

fia-chloro-N-androsten- 17a-0l-3-one.

fia-cholor-androstan- 17a-o1-3-one.

6a-ch1oro-19-nor-A androsten-17a-o1-3-one.

Example VI Example 11 was repeated but using androstan 17oc-O1-3- one as starting material, thus producing 13ot-fluoro-175- methyl 18 nor androstan 3 one, 175 methyl 18 nor A androsten 3 one, 175 fluoro androstan 3 one and 17a chlorofiuoroacetoxy androstan-3-one.

Example VII In accordance with the method described in Example III, 2 g. of 17a-estradiol-3-methyl-ether were treated with 2-chloro-1,1,Z-trifiuorotriethylamine in acetonitrile, thus producing 3 methoxy 13cc fluoro 175 methyl A 18 nor estratriene, 3 methoxy 175 methyl A 18 nor estratetraene, 3 methoxy 175 fluoro Aid/5G0) estratriene and 3 methoxy 17oz chlorofluoroacetoxy A estratriene, which were separated by chromatography.

In a similar but using l-methyl-17u-estradiol-3-methylether as starting material there were produced 3-methoxy- 13a fluoro 1,175 dimethyl A 18 nor estratriene, 3 methoXy 1,175 dimethyl A 18 nor estratetraene, 3 methoxy 1 methyl 175 fluoro A estratriene and 3 methoxy 1 methyl 17m chlorofiuoroacetoxy Amiwo) estratriene.

8 I claim: 1. A compound of the following formula:

wherein R and R are selected from the group consisting of hydrogen and methyl; X is selected from the group consisting of hydrogen, methyl, chlorine and fluorine, and Z is selected from the group consisting of a double bond and a saturated linkage between C4, C-5.

2. 13a fluoro 175 methyl 18 nor A androsten-3-one.

3. 13a fluoro 175 methyl 18,19 bis nor A androsten-3-one.

4. 13a fluoro 175 methyl 18 nor androstan 3-one.

5. 2u,175 dimethyl 13cc fluoro 18 nor A androsten-3-one.

6. 20:,175 dimethyl a fluoro 18 nor androstan-3-one.

7. 6a,175 dimethyl 13a fluoro 18 nor A androsten-3-one.

8. 6oz chloro 13oz fluoro methyl 18 nor A -androsten-3-one.

9. 6a,13ot difluoro 175 methyl 18 nor A androsten-3-one.

10. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and methyl and R represents a lower alkyl group.

11. 3 methoxy 175 methyl 13a fluoro A 18-n0r-estratriene.

12. 3 methoxy 1,175 dimethyl 13cc fluoro A -18-nor-estratriene.

13. 175 methyl 18 nor A androsten 3 one.

14. 204,175 dimethyl 18 nor A androsten 3 one.

15. 60:,175 dimethyl 18 nor A androsten 3 one.

16. A process for producing 13x-fluoro-175-methyl-18- nor steroids of the androstane series which comprises treating a 17a-hydroXy-androstane compound with 2- chloro-l,1,Z-trifluorotriethylamine.

Cross et al., J. Med. Chem, vol. 6, March 1963, pp. 198-200.

Knox et al., Tetrahedron Letters, No. 26, Dec. 1962, pp. 12491255.

LEWIS GOTTS, Primary Examiner. 

1. A COMPOUND OF THE FOLLOWING FORMULA: 